In the pharmaceutical industry, it often necessary to ascertain the rate at which a drug in solid form dissolves under certain, well-defined conditions. This process is known as in vitro drug dissolution testing, and is a critical component of pharmaceutical product and process development, as well as manufacturing. Dissolution testing can be used to study the drug release characteristics of a particular dosage form, to evaluate the quality control of the process used to form the drug, and to aid in pharmaceutical formulation development and stability determination. Furthermore, the robustness and uniformity of manufacturing batches are determined using dissolution tests. Consequently, the reproducibility and accuracy of the dissolution tests, as well as the identification of sources that may cause variability between tests, are of the utmost importance.
The United States Pharmacopoeia (USP) compendial ‘Apparatus’ used for drug dissolution testing are “Apparatus 1” (the basket method), ‘Apparatus 2’ (the paddle method), ‘Apparatus 3’ (the reciprocating cylinder), ‘Apparatus 4 (the flow-through cell), ‘Apparatus 5’ (the paddle over disk), ‘Apparatus 6’ (the cylinder) and ‘Apparatus 7’ (the reciprocating holder). It is important that the results of the dissolution test are accurate and reproducible. The accuracy and reproducibility of dissolution results is ensured through calibration of the dissolution apparatus. Calibration of a dissolution apparatus demonstrates the suitability of the use of that dissolution apparatus in a dissolution test, and is similar in concept to system suitability determinations for other analytical procedures (Foster, T., Brown, W.; USP Dissolution Calibrators: Re-examination and Appraisal; Dissolution Technologies (February 2005), pp 6-8 (Foster and Brown, 2005) incorporated herein by reference). To assess the suitability of a dissolution apparatus, the USP requires a combination of sufficiently detailed descriptions of the compendial testing apparatus, mechanical calibration, and a demonstration of suitable performance using standard reference materials (chemical calibration). These reference materials are currently in the form of calibrator tablets and include non-disintegrating salicylic acid tablets, and disintegrating prednisone tablets. Ideally, a calibrator tablet should: demonstrate that the entire system is working acceptably, provide an absolute standard for comparing dissolution testing apparatus, and confirm that the system works acceptably as a complement to mechanical calibration (Gray, V.; Barot, M. Bhattacharyya; P., Burmicz, J.; Crist, B., et al.; Activities of the USP Project Team on Dissolution Calibration. Dissolution Technologies (February 2005), pp. 35-36. (Gray et al., 2005) incorporated herein by reference).
Unfortunately, despite the reliance of the USP, the FDA and the industry on dissolution testing, there have been numerous reports in the literature describing high variability and unpredictability of test results, even for the dissolution apparatus calibrator tablets themselves. This variability of test results may result in an apparatus failing a validation test or a batch of drugs being rejected. False-negative calibrator test results lead to time and money being wasted through unnecessary investigation and re-calibration of dissolution apparatus. More concerning is that the false-negative calibrator test results raises doubts in the data obtained from the dissolution apparatus, often leading to additional expense and delay from unnecessary retesting of previous samples. Failed dissolution calibration tests resulted in 14 product recalls in 1999 and 20 product recalls in 2000 (Kukura, J.; Baxter, J. L.; Muzzio, F. J; Shear Distribution and Variability in the USP ‘Apparatus 2’ Under Turbulent Conditions; International Journal of Pharmaceuticals. 279; 2004; pp. 9-17 (Kukura et al., 2004) incorporated herein by reference). The financial consequences of a dissolution apparatus failing dissolution calibration tests can be significant for a pharmaceutical corporation, necessitating product recalls, costly investigations, potential product delays and even revalidation of the manufacturing process.
There are many sources of the variation of results for dissolution and calibration tests, and it is the role of the calibrator to detect these deviations. One main cause of variation is the hydrodynamics of the liquid within the vicinity of a tablet (either a drug or calibration tablet). Experiments have confirmed that dissolution rates can vary substantially when tablets experience different shear environments due to their locations within the device, and that uneven distribution of the hydrodynamic force is a direct cause of dissolution testing variability (Kukura et al., 2004). Variations in test results may also be caused by the apparatus itself including belt tightness, current surges, shaft wobble, basket imperfections, basket cleanliness, vessel cleanliness, vessel imperfections, vibration, and temperature fluctuations. Variations may further be introduced by the analyst, and may include improper apparatus setup, medium degassing, sample introduction, and sample preparation and filtration (Mirza, T.; Mechanical Versus Chemical Dissolution Calibration; Dissolution Technologies 2; Article 1; 2000. (Mirza, 2000) incorporated herein by reference). A high rate of variability has also been attributed to the calibrator tablets themselves. Thus, there are many different causes for variations of test results that might ultimately result in the failure of a test or apparatus.
There are a number of problems associated with the current methods and tools for the calibration of dissolution apparatus. The salicylic acid calibrator tablets are often found to be fused or chipped in bottles from current lots. These tablets are criticized for alleged insensitivity to perturbational variables related to “Apparatus 1” and ‘Apparatus 2’ (Foster and Brown, 2005). Furthermore, an argument has been made that there is variability in intrinsic performance of the USP calibrator tablets that has been found to be so great that it often exceeds the variability of the performance of modern dissolution test assemblies (Foster and Brown, 2005). Current dissolution apparatus calibration also interrupts the workflow from a test assembly, requiring a different medium and volume, and often a different apparatus speed for each of 2 separate calibrator tablets. This also means that it will take a long time for the completion of a dissolution calibration run, which will interfere with method development. Lastly, current dissolution calibrator tablets are not diagnostic tools that can determine the cause of failure for a dissolution test. The dissolution of a calibrator tablet is unable to pinpoint the cause of a deviation. A change in dissolution rate can be the culmination of many different effects, including the various causes discussed above. Thus, it is a challenge for the calibration of dissolution apparatus to ensure that the variation seen in multiple dissolution samples represents some intrinsic difference in the units tested and is not the cumulative effect of small differences in the dissolution test environment.
Therefore, there is a need for a method for calibration of dissolution apparatus that is sensitive to vibrations, stable, easy to manufacture in a consistent manner, has minimal toxicity, and can diagnose the cause of the dissolution apparatus failure. There is a further need for a method that improves calibration efficiency and allows for same-day or near-day calibration. There is a further need for a method that minimizes impact on the workflow from a dissolution apparatus. There is a further need for a method that allows for the evaluation of the hydrodynamic environment in the apparatus in order to eliminate this potential source of failure as it is unrelated to product quality. There is a further need for a method that is reproducible, re-usable and less expensive in the long term than the current use of calibrator tablets. There is an additional need for a method of calibration that is applicable to all of the different and accepted apparatus, including “Apparatus 4”, for which the USP does not provide calibration guidelines (Gray et al., 2005).
There also is a need for an apparatus to carry out the method for calibration of dissolution apparatus.